Thrombocytopenia in the First 24 Hours After Birth and Incidence of Patent Ductus Arteriosus

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Thrombocytopenia in the First 24 Hours After Birth

and Incidence of Patent Ductus Arteriosus

WHAT’S KNOWN ON THIS SUBJECT: To date, 4 small to moderate sized studies have revealed conflicting results on the clinically important question whether thrombocytopenia contributes to persistent patent ductus arteriosus (PDA) in very immature, preterm infants.

WHAT THIS STUDY ADDS: Thrombocytopenia in thefirst 24 hours after birth was not associated with the incidence of PDA at postnatal day of life 4 to 5 in a large cohort of preterm infants with,1500 g birth weight. Platelet dysfunction, rather than platelet number, might play a role in ductus arteriosus patency.

abstract

BACKGROUND: Experimental studies suggest that platelet-triggered ductal sealing is critically involved in definite ductus arteriosus closure. Whether thrombocytopenia contributes to persistently patent ductus arteriosus (PDA) in humans is controversial. This was a retrospective study of 1350 very low birth weight (VLBW; ,1500 g) infants, including 592 extremely low birth weight (ELBW;,1000 g) infants.

METHODS:All infants who had a platelet count in the first 24 hours after birth and an echocardiogram performed on day of life 4 to 5 were included. The incidence of thrombocytopenia was analyzed in infants with and without PDA, and in those who did or did not undergo PDA intervention. The impact of thrombocytopenia, gestational age, birth weight, gender, and sepsis on PDA was determined by receiver oper-ating characteristic curve, odds ratio, and regression analyses.

RESULTS:Platelet numbers within thefirst 24 hours after birth did not differ between VLBW/ELBW infants with and without spontaneous ductal closure. Platelet numbers were not associated with subsequent PDA treatment. Low platelet counts were not related to failure of pharma-cologic PDA treatment and the need for subsequent surgical ligation. Lower gestational age or birth weight, male gender, and sepsis were linked to the presence of PDA in VLBW infants on day of life 4 to 5.

CONCLUSIONS:Thrombocytopenia in thefirst 24 hours after birth was not associated with PDA in this largest VLBW/ELBW infant cohort studied to date. Impaired platelet function, due to immaturity and critical illness, rather than platelet number, might play a role in ductus arteriosus patency.Pediatrics2012;130:e623–e630

AUTHORS:Hannes Sallmon, MD,a,b,* Sven C. Weber, MD,a,c,*

Britta Hüning, MD,dAnja Stein, MD,dPeter A. Horn, MD,e

Boris C. Metze, MA,aChristof Dame, MD,aChristoph

Bührer, MD, PhD,aUrsula Felderhoff-Müser, MD, PhD,d

Georg Hansmann, MD, PhD,b,xand Petra Koehne, MDa,x

Department ofaNeonatology, andcGeneral Pediatrics, Charité

University Medical Center, Berlin, Germany;bDivision of Newborn

Medicine, Department of Pediatrics, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; anddDivision of

Neonatology, Department of Pediatrics I, andeInstitute for

Transfusion Medicine, University Hospital Essen, Essen, Germany

KEY WORDS

ductal closure, patent ductus arteriosus, preterm infant, platelets, very low birth weight

ABBREVIATIONS

COX—cyclooxygenase DA—ductus arteriosus DOL—days of (postnatal) life ELBW—extremely low birth weight NS—not significant

OR—odds ratio

PDA—patent ductus arteriosus ROC—receiver operating characteristic VLBW—very low birth weight

*Drs Sallmon and Weber contributed equally to this work asfirst authors.

xDr Hansmann and Dr Koehne contributed equally as senior

authors.

Dr Sallmon and Dr Hansmann wrote the manuscript; and all authors made substantial contributions to conception and design, acquisition of data, analysis, and interpretation of data. Thus, all persons designated as authors qualify for authorship, and all those who qualify are listed. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content. All authors commented on and/or revised the manuscript, and approved thefinal version.

www.pediatrics.org/cgi/doi/10.1542/peds.2012-0499

doi:10.1542/peds.2012-0499

Accepted for publication Apr 27, 2012

Address correspondence to Georg Hansmann, MD, PhD, Division of Newborn Medicine, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Ave, 02115 Boston, MA. E-mail: georg.hansmann@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE:The authors have indicated they have nofinancial relationships relevant to this article to disclose.

FUNDING:No external funding.

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,28 weeks of gestation.1 Physiologic

ductus arteriosus (DA) closure occurs in the first 3 days after birth.1–3 The

persistence of a PDA beyond thefirst postnatal days of life, however, is fre-quently associated with multiple severe complications, predominantly in the most immature infants. Depending on the degree of left-to-right ductal shunt-ing, an exaggerated postnatal increase in pulmonary bloodflow can cause left ventricular volume overload, pulmonary edema, and impairment of lung com-pliance, and may be associated with the development or progression of pulmo-nary vascular and chronic parenchymal lung disease.4 In addition,

cardiopul-monary deterioration with decreased systemic perfusion increases the risk of neonatal death.5 Recently, the

threshold for PDA intervention has been raised, given the high spontane-ous DA closure rate and low comor-bidity with small ductal shunt or mild symptoms.6 The exact indications for

PDA interventions are controversial.7

Therefore, understanding the risk fac-tors, disease mechanisms, and

modi-fiers that underlie DA closure is of pivotal clinical importance for tailored intensive care of preterm infants.

After birth, an increase in oxygen tension results in initial ductal constriction. Falling levels of prostaglandin E2 pro-mote functional DA closure (medial smooth muscle cell contraction that causes DA wall thickening, luminal obliteration, and shortening). The sub-sequent definite DA closure is charac-terized by vascular fibrosis due to an infolding of the endothelium, neointima formation, subintimal disruption, and vasa vasorum ingrowth. Although sev-eral molecular pathways (eg, nitric ox-ide, vascular endothelial growth factor, the cyclooxygenase [COX]/prostaglandin system8–11) are known to be involved

in permanent DA sealing, the complex

understood.12

Intriguingly, Echtler et al13 reported

that platelet-triggered ductal sealing (with subsequent vascular remodeling) seems to be an important mechanism for definite DA closure. In their mouse models, platelets were recruited to the endothelium of the DA soon after birth, and induced platelet dysfunction or defective platelet formation resulted in persistent PDA. Addressing the clinical implications, Echtler et al conducted a small retrospective study in 123 infants born at 24 to 30 weeks’gestation in a German tertiary center, and con-cluded that mild thrombocytopenia (platelet counts 101 000–140 000/mL) on thefirst day of life (DOL) was a risk factor for failure of DA closure.13

A subsequent small retrospective single-center study presented at the 2011 Pediatric Academic Societies’ meeting evaluated the association between platelet counts on DOL 1 to 3 and DA closure in 148 extremely low birth weight (ELBW;,1000 g) infants in the United States. Both spontaneous and indomethacin-induced DA closure were found to be less frequent in ELBW infants with platelet counts ,150 000/

mL (K. Dwarakanath, N.R. Dereddy, D. Chabra, C. Schabacker, J. Calo, L.A. Parton, unpublished data, 2011). How-ever, the latter study has confounders in the thrombocytopenic group, and 2 retrospective studies from Japan (142 born at 24–30 weeks’gestation)14 and

the United States (497 born at ,28 weeks’ gestation who received pro-phylactic indomethacin)15 did notnd

an association between thrombocyto-penia and incidence of PDA.

Because of the aforementioned contro-versy, we conducted a large retrospec-tive study in a cohort from 2 German tertiary centers including 1350 very low birth weight infant (VLBW) (,1500 g) infants, of whom 592 had ELBW. We

sociated with higher incidence of PDA in either VLBW or ELBW infants. In addi-tion, we found that sepsis, male gen-der, and lower gestational age or birth weight is associated with higher PDA incidence.

METHODS

Patients

This retrospective cohort study was

conducted at the NICUs in the

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PDA Diagnosis/Algorithm for PDA Intervention

Infants were evaluated for a hemody-namically significant PDA on DOL 4 to 5 and when clinically indicated. Echo-cardiographic studies included the assessment of ductal shunt direction by using color Doppler (high upper para-sternal short axis) and measurement of the minimal internal ductal diameter in B-mode (average of 3–5 measurements). The left atrium to aortic root ratio was determined by using M-mode in the parasternal long axis views. Doppler measurements of the resistance index in the anterior cerebral artery was conducted at the same time.

Imaging was performed by 3 experi-enced echocardiographers using HDI 3500 equipment (ATL Philips Medical Systems, Hamburg, Germany; ACUSON Sequoia 512, Siemens, Erlangen, Ger-many) with a curved array transducer (7.5–10 MHz).

In both study centers, COX inhibitor treatment was only initiated in VLBW/

ELBW infants with hemodynamically significant PDA (hsPDA). A PDA with left-to-right shunt was considered hemody-namically significant under the following conditions: (1) respiratory setback with supplemental inspiratory oxygen.30% and/or mechanical invasive or non-invasive ventilation; (2) left atrium to aortic root ratio$1.4 by using M-mode; and/or (3) ductal diameter $2.5 mm; and/or (4) a decreased end diastolic

flow in the anterior cerebral artery with a resistance index$0.85 in the cerebral ultrasound indicating significant ductal steal.

Although the center in Essen primarily used indomethacin for PDA intervention, in Berlin indomethacin was replaced by ibuprofen in April 2001 as an alter-native COX inhibitor with potentially fewer undesirable short-term adverse effects.16,17Due to the uncertain impact

of ibuprofen on bilirubin/albumin bind-ing capacity, the Berlin study center returned to indomethacin as the fi rst-choice drug in January 2005.5,18

Successful response to COX inhibitor treatment was defined as absence of ductal shuntflow 24 to 48 hours after the end of pharmacotherapy; all other cases were defined as COX inhibitor treatment failure. Ligation was per-formed as a rescue therapy in ventilated infants after failure of pharmacotherapy. Infants with successful pharmacologic closure of the PDA underwent routine echocardiography before discharge from the hospital.

COX Inhibitor Therapy

Infants received indomethacin, starting with 3 intravenous doses of 0.2 mg/kg per dose in 12-hour intervals followed by daily maintenance doses of 0.1 to 0.2 mg/kg for a maximum of 6 days. Ibu-profen (Pedea) was used with 3 doses of 10, 5, and 5 mg/kg per dose at 24-hour intervals to treat PDA according to the Safety Survey Report (Patient Use of Ibuprofen Orphan Europe/PEDEA Re-port IBU/SURVEY, April 2003).

Statistical Analysis

Values are expressed as absolute num-ber of patients and percentage unless stated otherwise. Demographic charac-teristics are given as median and range. Comparisons between groups were made by using Kruskal-Wallis or Mann-WhitneyUtests as appropriate for con-tinuously scaled data and by usingx2 tests for categorical data.Pvalues,.05 were considered statistically significant. Receiver operating characteristic (ROC) curves, odds ratios (ORs), and logistic multivariate regression analyses were conducted by using SPSS version 19 software (SPSS Inc, Chicago, IL).

RESULTS

Incidence of PDA

Of 1730 VLBW infants who were born in the respective period, 1350 VLBW infants (including 592 ELBW infants) met the inclusion criteria; 365 infants FIGURE 1

Study design. Theflowchart illustrates the numbers of VLBW and ELBW infants who were included in this retrospective cohort study. As shown (numbers given in parentheses), the ELBW population is a subset of the total VLBW infant cohort.

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were excluded because they either died early postnatally or data (complete blood cell count, echocardiography, or demographic data) were missing; 15 infants who underwent primary PDA ligation were also excluded (Fig 1). De-mographic characteristics are shown in Table 1 (total VLBW cohort) and Ta-ble 2 (ELBW subset). In the VLBW infant cohort, 657 (48.7%) of 1350 were male; of these 657 male infants, 408 (62.1%) had a PDA, 139 (21.2%) received phar-macologic PDA treatment, and 58 (8.8%) underwent secondary surgical ligation. The according relative pro-portions for female VLBW infants (693 of 1350 [51.3%]) were as follows: 352 (50.8%) of 693 had a PDA, 113 (16.3%) received pharmacologic PDA treatment, and 52 (7.5%) underwent secondary surgical ligation. The frequency of PDA was significantly higher in male versus female patients in both the total VLBW

cohort and the ELBW subset (Tables 1 and 2).

As expected, given the degree of im-maturity, the rate of PDA on DOL 4–5 was higher in the ELBW subset than in the total VLBW cohort (72.8% vs 56.3%, re-spectively). In addition, 63.6% (274 of 431) of all ELBW infants with PDA re-ceived treatment (pharmacologic COX inhibition with or without secondary surgical ligation) versus only 47.6% (362 of 760) of all VLBW infants. Failure of pharmacologic treatment (ie, secondary ligation) was observed in 36.5% ELBW (100 of 274) and 30.4% VLBW (110 of 362) infants.

Thrombocytopenia and PDA

Platelet counts did not differ between VLBW infants with and those without PDA. Platelet counts,150 000/mL were found in 16.8% versus 15.9% of VLBW infants, and in 19.3% versus 21.1% of

ELBW infants, with and without PDA, respectively (Tables 1 and 2). Among the 222 VLBW infants with thrombocy-topenia (platelet count ,150 000/mL) in thefirst 24 hours’ postnatally, 128 had a PDA (57.7%) whereas 632 (56.0%) of the 1128 nonthrombocytopenic infants had a PDA (not significant [NS]). A near-even distribution was also found in ELBW infants: PDA was evident in 91 (74.6%) of 122 and 340 (72.3%) of 470 of the thrombocytopenic and nonthrom-bocytopenic infants, respectively (NS). Lower gestational age and birth weight had significant effects on the prevalence of PDA, the need for therapy, and the rate of pharmacologic treatment failure in both VLBW and ELBW infants (Table 3).

Because thrombocytopenia could affect the need for PDA treatment or influence the success rate of treatment (pharma-cologic COX inhibition versus secondary ligation), we investigated platelet number

All VLBW 1350 (100) 590 (43.7) 760 (56.3) 252 (18.7) 110 (8.1) 398 (29.5)

Female 693 (51.3) 341 (57.8) 352 (46.3) 113 (44.8) 52 (47.3) 187 (47.0)

Male 657 (48.7) 249 (42.2) 408 (53.7) 139 (55.2) 58 (52.7) 211 (53.0)

BW, g 1060 (270–1495) 1230 (356–1495) 945 (270–1495) 870 (270–1495) 728 (360–1440) 1080 (382–1495) GA, wk 28 2/7 (22 0/7–37 3/7) 29 6/7 (22 0/7–37 3/7) 27 2/7 (22 6/7–35 1/7) 26 4/7 (23 0/7–32 0/7) 25 0/7 (23 0/7–30 6/7) 28 2/7 (22 6/7–35 1/7)

PLT.150/nL 1128 (83.6) 496 (84.1) 632 (83.2) 204 (81.0) 95 (86.4) 333 (83.7)

PLT,150/nL 222 (16.4) 94 (15.9) 128 (16.8) 48 (19.0) 15 (13.6) 65 (16.3)

PLT,100/nL 46 (3.4) 14 (2.4) 32 (4.2) 11 (4.4) 3 (2.7) 18 (4.5)

PLT,50/nL 16 (1.2) 6 (1.0) 10 (1.3) 4 (1.6) 1 (0.9) 5 (1.3)

Sepsis 54 (4) 12 (2.0) 42 (5.5) 25 (9.9) 6 (5.5) 11 (2.8)

Demographic characteristics and incidence of thrombocytopenia in the total cohort of infants with VLBW (birth weight [BW],1500 g). In the top row, data in parentheses represent percentages referring to the total number of 1350, included VLBW preterm infants (horizontal comparison within thefirst row). For all other data shown, percentages in parentheses refer to the total number in the upperfirst row of the same column (vertical comparison within the same column). Data are presented asn(%) or median, range. GA, gestational age; Pharm, pharmacologic therapy; PLT, platelet count.

TABLE 2 Demographic Characteristics and Incidence of Thrombocytopenia and Sepsis in the Subset of ELBW Infants

Characteristic ELBW Without PDA PDA PDA Pharm PDA Secondary Ligation PDA Without Therapy

All ELBW 592 (100) 161 (27.2) 431 (72.8) 174 (29.4) 100 (16.9) 157 (26.5)

Female 304 (51.4) 99 (61.5) 205 (47.6) 113 (64.9) 49 (49.0) 80 (51.0)

Male 288 (48.6) 62 (38.5) 226 (52.4) 61 (35.1) 51 (51.0) 77 (49.0)

BW, g 785 (270–998) 837 (356–995) 770 (270–998) 773 (270–995) 705 (360–990) 825 (382–998) GA, wk 26 2/7 (22 0/7–33 0/7) 27 1/7 (22 0/7–32 0/7) 26 0/7 (22 6/7–33 0/7) 26 0/7 (23 0/7–30 3/7) 24 6/7 (23 0/7–30 2/7) 26 6/7 (22 6/7–33 0/7)

PLT.150/nL 470 (79.4) 130 (80.7) 340 (78.9) 136 (78.2) 86 (86.0) 118 (75.2)

PLT,150/nL 122 (20.6) 31 (19.3) 91 (21.1) 38 (21.8) 14 (14.0) 39 (24.8)

PLT,100/nL 26 (4.4) 5 (3.1) 21 (4.9) 9 (5.2) 3 (3.0) 9 (5.7)

PLT,50/nL 7 (1.2) 1 (0.6) 6 (1.4) 3 (1.7) 1 (1.0) 2 (1.2)

Sepsis 38 (6.4) 7 (4.3) 31 (7.2) 22 (12.6) 6 (6.0) 3 (1.9)

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distributions in infants with PDA who subsequently were pharmacologically treated, ligated after treatment failure, and those who did not receive any specific treatment. As shown in Fig 2, platelet

counts did not differ between groups of VLBW and ELBW infants. Thus, platelet numbers were not associated with the frequency of PDA on DOL 4 to 5 or a spe-cific therapeutic intervention.

ROC Curve Analysis (Platelet Count, Gestational Age, and Birth Weight)

ROC curve analysis was performed to determine whether thrombocytopenia, birth weight, or gestational age show any association with PDA. We thus ruled out the possibility that low platelet counts of a certain threshold might be associated with PDA. Figure 3 shows ROC curve analyses for the associa-tions between platelet counts, birth weight, and gestational age with PDA in VLBW infants, by comparing infants with and without PDA. Lower birth weight and lower gestational age were associated with a higher PDA in-cidence, although platelet number did not seem to have any effect on PDA incidence. A ROC analysis for the ELBW subset revealed similar results (data not shown). Comparisons be-tween (1) infants with PDA who received treatment (pharmacologic treatment and secondary ligation) versus infants with PDA who did not receive treat-ment and (2) between infants with successful pharmacologic treatment versus infants who underwent sec-ondary ligation, with respect to effects of thrombocytopenia, birth weight, or gestational age are shown in Table 3. Although gestational age and birth weight were inversely associated with PDA on DOL 4 to 5, platelet number showed no such association (Fig 3).

Influence of Sepsis and Male Gender on PDA Frequency

Moreover, we calculated ORs for PDA and sepsis or male gender in VLBW and ELBW infants, respectively. There were significantly increased ORs (approximate relative risk) for PDA in VLBW infants for both variables (Table 4). In ELBW infants, only male gender was associated with an increased OR for PDA. Sepsis in-creased the OR for PDA that required specific treatment compared with PDA without the need for such intervention in both VLBW and ELBW infants. Finally,

TABLE 3 ROC Curve Analysis in the Total VLBW Infant Cohort and the ELBW Subset

Variable VLBW ELBW

Platelet number

PDA versus no PDA 0.483 (0.452–0.514) 0.499 (0.447–0.551) PDA (therapy) versus PDA (no therapy) 0.487 (0.445–0.528) 0.494 (0.434–0.553) PDA (pharma) versus PDA (secondary ligation) 0.541 (0.475–0.606) 0.564 (0.497–0.640) Birth weight

PDA versus no PDA 0.709a(0.6810.737) 0.597a(0.5450.690)

PDA (therapy) versus PDA (no therapy) 0.736a(0.7000.771) 0.635a(0.5790.690)

PDA (pharma) versus PDA (secondary ligation) 0.701a(0.6460.756) 0.639a(0.5750.704)

Gestational age

PDA versus no PDA 0.752a(0.6550.710) 0.661a(0.6110.711)

PDA (therapy) versus PDA (no therapy) 0.771a(0.7380.804) 0.729a(0.6800.778)

PDA (pharma) versus PDA (secondary ligation) 0.757a(0.7030.810) 0.724a(0.6630.785)

The ELBW population is a subset of the total VLBW cohort. Data are presented as area under the curve (95% confidence interval). pharma, pharmacologic therapy.

aStatistically signicant.

FIGURE 2

Boxplot: platelet count distribution. Boxplots show platelet count distributions within thefirst 24 hours of life with median and the 25th and 75th percentiles among 4 different groups of VLBW (white) and ELBW (gray) infants: PDA with pharmacologic (pharm) therapy, PDA with secondary (sec) ligation, PDA without therapy, and no PDA. There were no significant differences between the 4 groups in VLBW and ELBW infants, respectively. Of note, the ELBW population is a subset of the total VLBW infant cohort.

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regression analyses in VLBW infants confirmed that sepsis, male gender, and gestational age are independent pre-dictors of PDA (data not shown).

DISCUSSION

Because of controversial data on the relationship between platelet number and PDA frequency,13–15we performed a large retrospective study at 2 tertiary centers to investigate higher numbers of VLBW/ELBW infants, with balanced gender

ratio and similar ethnic background compared with the study published by Echtler et al.13We herein report platelet

numbers, PDA incidence, and PDA in-tervention in the largest VLBW (n= 1350; median gestational age: 28 2/7 weeks) and ELBW (n= 592; median gestational age: 26 2/7 weeks) cohorts published to date. In our study, the estimated in-cidence of PDA on DOL 4 to 5 (56% of all VLBW infants), frequency of PDA phar-macotherapy (27%), and secondary PDA ligation (8%) was within the (wide)

We found that mild (,150 000/mL), mod-erate (,100 000/mL), or severe (,50 000/mL) thrombocytopenia in thefirst 24 hours after birth was not associated with a higher incidence of PDA in either VLBW or ELBW infants not prophylactically trea-ted with either indomethacin or ibuprofen. However, sepsis and lower gestational age or birth weight were associated with a higher PDA incidence.

In contrast to the previously published small retrospective, single-center study by Echtler et al,13which demonstrated an

association between moderate throm-bocytopenia and frequency of PDA (123 infants born at 24–30 weeks’gestation), and preliminary data (K. Dwarakanath, N.R. Dereddy, D. Chabra, C. Schabacker, J. Calo, L.A. Parton, unpublished data, 2011), 2 very recent retrospective stud-ies from Japan14and the United States15

did not find such an association. How-ever, the moderately sized US study by Shah et al15focused on the relation

be-tween platelet numbers and DA closure after prophylactic indomethacin treat-ment within thefirst 15 hours after birth (497 infants,28 weeks’gestation), and the other 2 published studies13,14 are

hampered by a relatively small sample size, as well as different ethnic back-ground and gender distribution14in the

cohorts studied.22 The yet unpublished

report by Dwarakanath et al (2011) is confounded by lower average birth weight, higher rates of intrauterine growth re-tardation, and maternal preeclampsia in the thrombocytopenic infants.

Although the study by Fujioka et al14

revealed results similar to ours, it has been particularly criticized for its small sample size (N= 142) and an apparent unbalanced gender ratio in infants with low platelet counts (n= 16; 84% males). In contrast, both our thrombocytopenic and nonthrombocytopenic VLBW pop-ulation had a balanced gender ratio (thrombocytopenic males: 28 of 48 FIGURE 3

ROC curve analyses. Representative ROC curves for platelet count, birth weight, and gestational age comparing VLBW infants with and without PDA. The platelet curve divides the plot into 2 almost equal parts (indicating no association with PDA),. In contrast, the ROC curves for birth weight and gestational age show an unequal division resulting in an area under the curve.0.5, indicating a negative cor-relation of gestational age or birth weight with PDA incidence. Similar results were obtained in the ELBW population, which is a subset of the total VLBW infant cohort (data not shown).

TABLE 4 OR Analysis in the Total VLBW Infant Cohort and the ELBW Subset

Variable VLBW ELBW

Sepsis

PDA versus no PDA 2.82a(1.475.40) 2.07 (0.855.05)

PDA (therapy) versus PDA (no therapy) 3.30a(1.636.66) 4.35a(1.5012.65)

PDA (pharma) versus PDA (secondary ligation) 1.91 (0.76–4.79) 2.27 (0.89–5.8) Male gender

PDA versus no PDA 1.64a(1.322.04) 1.76a(1.222.56)

PDA (therapy) versus PDA (no therapy) 1.07 (0.80–1.42) 1.24 (0.84–1.84) PDA (pharma) versus PDA (secondary ligation) 1.12 (0.72–1.76) 1.24 (0.76–2.03)

The ELBW population is a subset of the total VLBW cohort. Data are presented as OR (95% confidence interval). pharma, pharmacologic therapy.

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[58.3%]; nonthrombocytopenic males: 626 of 1302 [48.1%]; NS). Notably, Ech-tler et al13argue that, in contrast to

their own study, Fujioka et al only in-cluded Asian infants and, therefore, ethnic differences might have contrib-uted to the contradictory results.14

The VLBW/ELBW infants in our study (N= 1350) and those studied by Ech-tler et al (N = 123) were born in the same country at tertiary centers, had a predominately caucasian ethnic back-ground, and a similar in utero environ-ment. Thus, potential differences in NICU management or ethnicity cannot explain the discrepancy in thefindings.

Shah et al15assessed serial platelet

counts (DOL 1 to 7) in preterm infants born,28 weeks’gestation, all of whom received prophylactic indomethacin starting on DOL 1. Patency of DA was not related to platelet count at any time in the first week of life. Instead, high platelet numbers may have been asso-ciated with initial DA constriction/ closure. Neither high nor low platelet numbers had an impact onfinal, per-manent DA closure. However, the

in-fluence of platelet numbers on DA in the absence of indomethacin could not be determined in the study by Shah et al. We also did notfind an association be-tween platelet number in the first 24 hours after birth and PDA on DOL 4 to 5

in VLBW/ELBW preterm infants, regard-less of whether the infants had sub-sequently received pharmacologic COX inhibition, secondary ligation, or no therapy (Fig 2). Moreover, when we used the exact same inclusion criteria as Echtler et al13(2430 weeks

gesta-tion), we still did notfind any associa-tion between platelet number and PDA (n= 947; data not shown).

Our study did not reveal an association between thrombocytopenia and PDA incidence, but sepsis, lower gesta-tional age, and lower birth weight were independent risk factors for DA patency. Interestingly, all the latter variables may affect platelet func-tion.23,24Given thendings on

platelet-triggered ductal sealing in mice,13we

speculate that platelet dysfunction (due to immaturity2527or critical

ill-ness23,24,28) rather than platelet

num-ber contributes to the pathogenesis of PDA.22

Although the platelet numbers reported in our study were determined in thefirst 24 hours after birth, and before any indomethacin or ibuprofen adminis-tration, we cannot rule out that a platelet nadir occurred on DOL 2 to 5, which may have influenced the effi -ciency of COX inhibition or the need for secondary surgical ligation in infants

with hemodynamically significant PDA, especially when other risk factors such as sepsis/inflammation were present. However, the data reported by Shah et al15 argue against the assumption

that a platelet nadir after thefirst 24 hours may have influenced PDA closure rate in our study because no associa-tion between platelet number at any time in the first week of life and DA patency or permanent closure was found.15 Furthermore, correction of

thrombocytopenia by transfusions or medications that alter hemostasis and platelet function such as ampicillin29

are unaccounted for in our retrospec-tive study. These open questions should be addressed by prospective studies that must include variables of platelet function to shed light on the current controversy about the causal role of platelets in DA closure.

CONCLUSIONS

We show that mild, moderate, or severe thrombocytopenia in thefirst 24 hours after birth is not associated with a higher rate of PDA in a large cohort of VLBW and ELBW infants, the vast majority of whom were born at 26 to 28 weeks’gestation. Impaired platelet function, due to im-maturity and critical illness, rather than platelet number, may contribute to DA patency.

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DOI: 10.1542/peds.2012-0499 originally published online August 6, 2012;

2012;130;e623

Pediatrics

and Petra Koehne

Hansmann

Metze, Christof Dame, Christoph Bührer, Ursula Felderhoff-Müser, Georg

Hannes Sallmon, Sven C. Weber, Britta Hüning, Anja Stein, Peter A. Horn, Boris C.

Ductus Arteriosus

Thrombocytopenia in the First 24 Hours After Birth and Incidence of Patent

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DOI: 10.1542/peds.2012-0499 originally published online August 6, 2012;

2012;130;e623

Pediatrics

and Petra Koehne

Hansmann

Metze, Christof Dame, Christoph Bührer, Ursula Felderhoff-Müser, Georg

Hannes Sallmon, Sven C. Weber, Britta Hüning, Anja Stein, Peter A. Horn, Boris C.

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Figure

FIGURE 1Study design. The flowchart illustrates the numbers of VLBW and ELBW infants who were included inthis retrospective cohort study

FIGURE 1Study

design. The flowchart illustrates the numbers of VLBW and ELBW infants who were included inthis retrospective cohort study p.3
TABLE 1 Demographic Characteristics and Incidence of Thrombocytopenia and Sepsis in all VLBW Infants (Total VLBW Cohort)

TABLE 1

Demographic Characteristics and Incidence of Thrombocytopenia and Sepsis in all VLBW Infants (Total VLBW Cohort) p.4
TABLE 2 Demographic Characteristics and Incidence of Thrombocytopenia and Sepsis in the Subset of ELBW Infants

TABLE 2

Demographic Characteristics and Incidence of Thrombocytopenia and Sepsis in the Subset of ELBW Infants p.4
TABLE 3 ROC Curve Analysis in the Total VLBW Infant Cohort and the ELBW Subset

TABLE 3

ROC Curve Analysis in the Total VLBW Infant Cohort and the ELBW Subset p.5
FIGURE 2an increased OR for PDA. Sepsis in-Boxplot: platelet count distribution. Boxplots show platelet count distributions within the first 24 hourscreased the OR for PDA that required

FIGURE 2an

increased OR for PDA. Sepsis in-Boxplot: platelet count distribution. Boxplots show platelet count distributions within the first 24 hourscreased the OR for PDA that required p.5
FIGURE 3

FIGURE 3

p.6
TABLE 4 OR Analysis in the Total VLBW Infant Cohort and the ELBW Subset

TABLE 4

OR Analysis in the Total VLBW Infant Cohort and the ELBW Subset p.6